Heart disease is a leading cause of death for men and women of all racial and ethnic backgrounds. Every year, approximately 1.2 million people will have a heart attack, while a further 500,000 individuals suffer from strokes. However, modern medicine has identified several therapeutic treatments to deal with the accumulation of platelets that are indicative of these diseases.
Anti-platelet therapies are commonly used in patients and tend to include aspirin, P2Y12 antagonists (e.g., Plavix [clopidogrel]) and the PAR1 antagonist vorapaxar. PAR4 is implicated with regard to treating certain cardiovascular diseases including thrombosis, coronary artery disease, cerebrovascular disease and neurological or pulmonary diseases that are mediated through the activation of thombin on the PAR4 receptor. PAR4, variance is highly conserved among generic populations and the Ala120Thr variant is very common in the population, with black subjects having a high allele frequency of Thr120, while whites have a high frequency of Ala120. Unfortunately, most patients treated with current anti-platelet therapies have recurrent vascular events and better treatments are needed.
Indeed, the “gold standard” and FDA-approved anti-platelet drugs are not as effective at inhibiting in vitro platelet aggregation from individuals expressing PAR4 Thr 120. Furthermore, anti-platelet therapies such as clopidogrel (PLAVIX®) are selective towards inhibiting platelet aggregation for individuals expressing PAR4 Ala120 but are not effective with regard to individuals expressing PAR4 Thr120. The limits of these therapies provide that patients should be tested to determine their genetic profile before they begin a treatment, so as to determine whether the treatment is likely to have any efficacy. For those who have the PAR4 Thr120 isoform, they are further burdened by lack of efficacy and options for treatment, thus disproportionally hurting a portion of the population over the other.
It has been previously disclosed that the compound YD-3 has been known to be a PAR4 antagonist, effective for the PAR4 Ala120 isoform and in human blood platelets stimulated with thrombin peptides that specifically activate PAR4. However, the PAR4 Thr120 isoform was relatively resistant to YD-3 inhibition, as well as all other commonly used anti-platelet drugs. Therefore individuals expressing the PAR4 Thr120 isoform do not receive optimal anti-platelet therapy compared to individuals who express only the Ala120 isoform. This has resulted in a discrepancy in the effectiveness of current therapies, based on the isoform of the PAR4 gene of the patient.
Therefore, new therapeutic compounds and compositions are necessary to provide universal treatment to patients, regardless of the PAR4 120 isoform. Specifically, such compounds and pharmaceutical compositions containing said compounds can be further utilized in methods of treatment that do not depend on the isoform of the PAR4 receptor for efficacy.